About the Project

Vision and Strategy

Toxicity testing typically involves studying adverse health
outcomes in animals subjected to high doses of toxicants with subsequent
extrapolation to expected human responses at lower doses. The system relies on
the use of a 40+year-old patchwork of animal tests that are expensive (costing
more than $3B per year), time-consuming, low-throughput and often provide
results of limited predictive value for human health effects. The low-throughput
of current toxicity testing approaches (which are largely the same for
industrial chemicals, pesticides and drugs) has led to a backlog of more than
80,000 chemicals to which humans are potentially exposed whose potential
toxicity remains largely unknown. In 2007, the National Research Council (NRC)
released the report "Toxicity Testing in the 21st Century: A Vision and a
Strategy", that charted a long-range strategic plan for transforming
toxicity testing. The major components of the plan include the use of
predictive, high-throughput cell-based assays (of human origin) to evaluate
perturbations in key toxicity pathways, and to conduct targeted testing against
those pathways. This approach will greatly accelerate our ability to test the
vast "storehouses" of chemical compounds using a rational, risk-based
approach to chemical prioritization, and provide test results that are
hopefully far more predictive of human toxicity than current methods. Although
a number of toxicity pathways have already been identified, most are only
partially known and no common annotation exists. Mapping the entirety of these
pathways (i.e. the Human Toxome) will be a large-scale effort, perhaps on the
order of the Human Genome Project.

Here, we propose to comprehensively map pathways of
endocrine disruption, representing a first step towards mapping the human
toxome. We will leverage our rapidly evolving scientific understanding of how
genes, proteins, and small molecules interact to form molecular pathways that
maintain cell function, applying orthogonal "omics" approaches
(transcriptomics, metabolomics) to map and annotate toxicity pathways for a
defined set of endocrine disruptors. Following the identification of toxicity
pathways, we will conduct a series of stakeholder workshops to enable the development
of a consensus-driven process for pathway annotation, validation, sharing and
risk assessment, and develop a public database on toxicity pathways, providing
a common, community-accessible framework that will enable the toxicology
community at large to comprehensively and cooperatively map the human toxome
using integrated testing strategies. Finally we will validate the identified
pathways of toxicity and extend the concepts to additional toxicants, cell
systems and endocrine disruptor hazards as well as to additional omics
platforms and to dose response modeling.